Survival and neurological outcome after sudden cardiac arrest (CA) remain very poor. Our prior work focused on understanding the return of neuro-electrical activity after CA and led to the discovery of a) quantitative signal processing methods that track brain injury and recovery after CA, b) recovery of thalamocortical networks during restitution of arousal after CA and c) the patterns of electrical rhythms and time course when therapy may impact recovery. Recent clinical reports demonstrate compelling therapeutic benefits of hypothermia following CA and a better understanding of the role of the thalamus in chronic disorders of consciousness after CA. Our proposal harnesses these opportunities to uncover the acute neurophysiologic mechanisms of arousal post-CA to develop clinically applicable diagnostic methods and optimize therapeutic hypothermia delivery.
The specific aims of this project are:
Aim 1 : We will discover the clinically relevant and neurophysiologically validated electrical markers of arousal from coma after CA. We will test the hypotheses that a) coma is marked by abnormal coupling of thalamic and cortical potentials, b) quantitative analysis of cortical somatosensory evoked potentials (SSEP) will track recovery of normal thalamocortical coupling, and c) entropy-based quantitative EEG (qEEG) analysis will capture sequential changes in thalamocortical coupling during recovery from CA injury.
Aim 2 : We will study the mechanism by which induced hypothermia results in enhanced neurophysiologic recovery. We will test the hypotheses that a) multi-unit (MU) recording from thalamus and cortex will demonstrate accelerated normalization of thalamocortical coupling with induced hypothermia, b) hypothermia accelerates normalization of SSEP indicating restoration of the subcortical pathway, and c) normalization of qEEG signals recovery of cortical function.
Aim 3 : Most advances in hypothermia are blindly directed toward faster cooling, without objective indicators of the brain's response to temperature. We will test the hypothesis that the depth and duration of hypothermia can be objectively titrated to non-invasive qEEG and SSEP markers of thalamocortical coupling in order to maximize brain recovery. This multifaceted approach - starting with direct multiunit recordings of thalamocortical components of the arousal system followed by non-invasive evoked potential and EEG monitoring - will allow for the comprehensive development of real-time neurophysiologic tools to titrate hypothermia treatment. The first phase of our basic research has already spawned an NIH-sponsored Phase IIB multi-center clinical trial. Our quantitative, neuroelectrophysiology-guided optimization of hypothermia delivery should be similarly applicable to monitoring patients and guiding induced hypothermia clinical trials in the near future.
The focus of the present proposal is on translational research: to study the problem of global ischemic brain injury following cardiac arrest (CA) and develop monitoring technologies for neuro-electrical markers of coma and arousal after CA. The basic research pertains to developing quantitative electrical measures of injury and understanding the cortical and subcortical origins of these signals. The translational research pertains to optimizing the procedure for induced hypothermia after CA using electrical signal measures. The innovation of this project lies in the comprehensive and novel application of quantitative methods, namely cortical (electroencephalography, EEG), subcortical (evoked potentials, EP), and multi-unit (MU) recordings to track injury and recovery. Our work has compelling translational applications: to monitor brain injury after CA in patients and to optimize hypothermia delivery after CA guided by neurological monitoring.
|Greenwald, Elliot; Maier, Christoph; Wang, Qihong et al. (2017) A CMOS Current Steering Neurostimulation Array With Integrated DAC Calibration and Charge Balancing. IEEE Trans Biomed Circuits Syst 11:324-335|
|Greenwald, Elliot; Masters, Matthew R; Thakor, Nitish V (2016) Erratum to: Implantable neurotechnologies: bidirectional neural interfaces--applications and VLSI circuit implementations. Med Biol Eng Comput 54:19-22|
|Ng, Kian Ann; Greenwald, Elliot; Xu, Yong Ping et al. (2016) Implantable neurotechnologies: a review of integrated circuit neural amplifiers. Med Biol Eng Comput 54:45-62|
|Greenwald, Elliot; Masters, Matthew R; Thakor, Nitish V (2016) Implantable neurotechnologies: bidirectional neural interfaces--applications and VLSI circuit implementations. Med Biol Eng Comput 54:1-17|
|Greenwald, Elliot; So, Ernest; Wang, Qihong et al. (2016) A Bidirectional Neural Interface IC With Chopper Stabilized BioADC Array and Charge Balanced Stimulator. IEEE Trans Biomed Circuits Syst 10:990-1002|
|Sun, Yu; Thakor, Nitish (2016) Photoplethysmography Revisited: From Contact to Noncontact, From Point to Imaging. IEEE Trans Biomed Eng 63:463-77|
|Manno, Edward M; Freeman, William D; Livesay, Sarah et al. (2016) Expertise Matters. Crit Care Med 44:e1147-e1148|
|Stupple, Aaron; Geocadin, Romergryko G; Celi, Leo Anthony (2016) Conversation prior to resuscitation: The new CPR. Resuscitation 99:e3|
|Kowalski, Robert G; Buitrago, Manuel M; Duckworth, Josh et al. (2015) Neuroanatomical predictors of awakening in acutely comatose patients. Ann Neurol 77:804-16|
|Schreck, Karisa C; Schneider, Logan; Geocadin, Romergryko G (2015) Clinical Reasoning: A 44-year-old woman with rapidly progressive weakness and ophthalmoplegia. Neurology 85:e22-7|
Showing the most recent 10 out of 64 publications